A number sign (#) is used with this entry because of evidence that infantile hypotonia with psychomotor retardation and characteristic facies-2 (IHPRF2) is caused by homozygous or compound heterozygous mutation in the UNC80 gene (612636) on chromosome 2q34.

Infantile hypotonia with psychomotor retardation and characteristic facies-2 is a severe autosomal recessive neurodevelopmental disorder with onset at birth or in early infancy. Affected individuals show severe global developmental delay with poor or absent speech and absent or limited ability to walk. Some patients may have seizures that can be controlled; brain structure is typically normal (summary by Shamseldin et al., 2016).

For a general phenotypic description and a discussion of genetic heterogeneity of infantile hypotonia with psychomotor retardation and characteristic facies, see IHPRF1 (615419).

Stray-Pedersen et al. (2016) reported 4 girls, ranging in age from 4 to 15 years, from 3 unrelated families with a severe neurodevelopmental disorder. Two patients were born of consanguineous parents of Iraqi and Moroccan descent, respectively, and 2 sibs were born of unrelated Norwegian parents. All patients presented at birth or in early infancy with severe persistent hypotonia, severe global developmental delay resulting in profound intellectual disability with no speech and motor skills ranging from inability to sit independently to walking with support. All had feeding difficulties necessitating gastric tube insertion, constipation, and failure to thrive. Head circumference was decreased. All had seizures of various types, including generalized tonic-clonic, atonic, and absence, that could be controlled with medication. EEG showed an encephalopathic background pattern with spike and wave discharges. Brain imaging in 1 patient showed generalized cerebral atrophy, thin corpus callosum, and decreased myelination, although imaging was normal in the other 3 patients. Dysmorphic features were mild and not consistent, but included brachycephaly, hypotonic facies with ptosis, esotropia, epicanthal folds, bulbous nasal tip, low-set ears, and joint laxity. Other features included small hands and feet and hypersensitivity to stimuli. Two patients had sleep disturbances.

Shamseldin et al. (2016) reported 6 living children from 4 unrelated consanguineous families with IHPRF2. All had severe axial hypotonia, profound developmental delay with very poor or absent speech, and failure to thrive. One patient had appendicular spasticity. Three patients had microcephaly (-3 to -4 SD), and all had minor dysmorphic features, such as plagiocephaly, brachycephaly, high forehead, strabismus, nystagmus, prominent nasal bridge, tented upper lip, and open mouth. Brain imaging of 1 patient showed diffuse brain atrophy. None had epilepsy, although 1 patient had a single seizure; EEG in 3 patients was abnormal and suggestive of an encephalopathy.

Perez et al. (2016) reported 7 children from 2 remotely related consanguineous Bedouin families with IHRPF2. All presented soon after birth with marked hypotonia and failure to thrive, and subsequently showed significant global developmental delay with almost no acquisition of developmental milestones. The patients had no social or verbal skills and were unable to sit or ambulate independently. Muscle disuse atrophy became apparent with age. Some had hyperactive reflexes, and all had mild dyskinesia, including choreoathetosis and dystonia. Four patients had generalized tonic seizures that could be controlled with medication; EEG showed disorganized background activity with nonspecific sharp and slow waves. Dysmorphic features were mild and variable, but included plagiocephaly, triangular face with frontal bossing, high nasal bridge with anteverted nasal tip, short smooth philtrum, downslanting palpebral fissures, posteriorly rotated low-set ears, thin upper lip, short neck, and scoliosis. Most lacked visual fixation and had esotropia and strabismus. Brain imaging showed no specific abnormal findings, except for mild ventricular enlargement in 2 patients.

The transmission pattern of IHRPF2 in the families reported by Stray-Pedersen et al. (2016) was consistent with autosomal recessive inheritance.

In 4 girls from 3 unrelated families with IHPRF2, Stray-Pedersen et al. (2016) identified biallelic mutations on the UNC80 gene (612636.0001-612636.0004). The mutations, which were found by exome sequencing, were predicted to result in a loss of function. In vitro studies of 1 of the mutations (P1700S; 612636.0001) showed that it was expressed normally and associated with UNC79 (616884) and NALCN (611549), but patch-clamp recording studies showed that the variant had significantly reduced NALCN currents compared to wildtype.

In 6 living children from 4 unrelated consanguineous families with IHPRF2, Shamseldin et al. (2016) identified 3 different homozygous mutations in the UNC80 gene (612636.0005-613636.0007). Two of the mutations were truncating and 1 was missense. Functional studies of the variant and studies of patient cells were not performed.

In 7 children from 2 distantly related consanguineous Bedouin families with IHPRF2, Perez et al. (2016) identified a homozygous nonsense mutation in the UNC80 gene (R51X; 612636.0008). The mutation, which was found by a combination of homozygosity mapping and whole-exome sequencing, segregated with the disorder. Western blot analysis of cells transfected with the mutant transcript showed absence of the UNC80 protein, consistent with a loss of function.